Microcavity-containing polymeric medical devices for enhanced ultrasonic echogenicity

ABSTRACT

An ultrasound-detectable polymeric device that offers superior visibility of the body of the device and decreased ultrasound angle dependence through the use of microcavities and methods of manufacturing thereof is disclosed. These microcavities enable superior ultrasound visualization due to diffuse reflection of sound waves when compared to solid polymeric objects, ensuring that a strong signal is received at the source of the ultrasound transducer and providing strong image contrast throughout the entire cross-section of the implant that is also robust to variable angles of insonation.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/209,082, filed Jul. 13, 2016, which claims the benefit of U.S.Provisional Application No. 62/193,380, filed Jul. 16, 2015, all ofwhich are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The presently disclosed subject matter relates generally to the designof polymeric medical devices which contain specially designedmicrocavities to generate improved echogenicity characteristics whenvisualized within the human body using ultrasound.

BACKGROUND

Noninvasive medical methods such as ultrasound imaging offer tremendousmedical value and point-of-care utility for diagnosis and measurement.It often is desirable to locate a medical device which is currentlywithin the human body or to identify a site where a procedure ormeasurement has been previously performed. However, interpretation ofgreyscale (B-mode) ultrasound requires expertise and it may be difficultto use native landmarks to determine whether the desired location hasbeen reached. For example, returning to the site of a prior procedurecan be challenging because of first, the difficulty in locating thepostoperative site and second, the difficulty in determining theorientation of the image vis-à-vis earlier images collected in order toaccurately analyze data collected from the location.

For the visualization of devices placed within the human body, manymethods of rendering surfaces echogenic have been described. The goal ofthese modifications is often to make an edge (such as the edge of ametal needle) more easily visualized under ultrasound. Such methods mayinclude machining small divots into the surface of the edge in order toreflect sonic waves in multiple directions. However, such methods aregenerally applicable only to metallic surfaces where the significantimpedence difference between metal and human tissue means that themajority of ultrasound waves will be reflected back from thetissue-metal surface towards the transducer and will not penetrate themetallic material. For materials which are closer in acoustic impedenceto human tissue, such as most polymers of medical interest, most of theultrasound waves will pass through the polymer, generating detectablesignals only at the entry and exit point of the waves. Based on ourexperimentation, any such surface modification attempts will fail tosignificantly increase the echogenicity of polymer devices. Similarly,attempts to create divots or indentations either randomly distributedacross the device body or penetrating through the entire thickness ofthe device (e.g., from the front to back surface of the device) fail toimprove echogenicity as desired.

Ultrasound tissue marker devices do exist within the medical devicelandscape for use in localizing sites within the body but areundesirable for certain applications because they lack such an echogenicenhancement method. These markers are often composed of a large surfacearea to volume ratio (e.g., they may be made up of many small pelletswhich may be randomly oriented) because the increased surface areamaximizes the return of ultrasound waves. If the thickness of the markerbody (i.e., the axis perpendicular to the beam direction) is largerelative to the ultrasound wavelength, only the device edges and not theinterior will be visualized. This is because substantial changes ineither density or compressibility do not exist throughout the volume ona microscopic scale. For both the purposes of human visualization aswell as medical imaging algorithm detection, it would often be desirableif a method were available to visualize the entire object underultrasound rather than just the edges.

Another significant problem relates to the angle of insonationdependence with respect to the ultrasound. Devices which rely onedge-only reflectance (e.g., the previously mentioned existing markers)function as largely specular reflectors which reflect the ultrasoundbeam according to the standard laws of reflection. While this isdesirable when the surface is perpendicular to the angle of insonation(because the strongest reflections are back towards the transducer), asthe angle of insonation begins to change towards parallel most of theultrasound energy reflects away from the transducer and is lost, makingthe surface dark and causing loss of the contrast necessary to visualizethe object.

Therefore, what is desired is a method of producing polymer-comprisedmedical devices which are 1) visualized throughout their entirethickness rather than just their edges as well as 2) more tolerant ofvariable insonation angles while still producing echogenic contrastcompared to surrounding tissue.

SUMMARY

The presently disclosed subject matter provides an ultrasound-detectablepolymeric medical device with superior visibility of the body of thedevice and less ultrasound angle dependence. These desirablecharacteristics are created by introducing controlled microcavitieswithin the marker to alter the reflection mechanism of the ultrasoundwaves as they pass through the implant.

The cavities have two main purposes: (a) creating differences in densityand compressibility within the marker on a small scale, and (b) creatingdiffuse reflection robust to insonation angle as compared to what isotherwise largely specular reflection. The small-scale density changesensure that acoustic signal reflections occur throughout the depth ofpenetration. The distance over which these changes occur is tuned to berelative to the wavelength of the ultrasound, with optimalcavity-polymer transitions occurring at distances comparable to theultrasound wavelength. The proper choice of microcavity ratio anddimension is essential because creation of excessive acoustic impedencewill cause premature absorption of all the ultrasound energy and failureof the object to fully illuminate, while inadequate impedence willresult in the internal structure being inadequately echogenic.

However, production of density changes alone simply create greaterreflections in the body of the object. For example, production of theobject using an additive manufacturing process such as 3D printingyields objects with a series of layers which may cause impedencechanges. However, such methods result in impedence changes that continueto be specular reflectors and result in objects seen best whenperpendicular to the source of the sound wave. This renders itimpossible to ever fully visualize a 3-dimensional shape where somesurfaces are not perpendicular to the ultrasound beam (for example, thesides of a sphere will not show up well).

In order to accommodate various orientations of geometric shape that maybe desired in, for example, an ultrasound marker device, themicrocavities and their essentially random surface orientation vis-à-visthe ultrasound beam will reflect the signal in a diffuse manner. Thusthe acoustic signal from the object returns to the probe irrespective oforientation and causes the whole cross-section of the object to appearvisible on the ultrasound screen.

In other aspects, the presently disclosed subject matter provides amethod for inserting and visualizing a medical device containingmicrocavities, the method comprising: (a) inserting a polymeric medicaldevice with microcavities into a patient; (b) visualizing and detectingthe device using B-mode ultrasound during or after surgery; and (c)performing this visualization in multiple near-simultaneous frames,representing different angles of insonation.

This method of detecting the medical device from multiple angles ofinsonation is of particular importance. In many clinical environments,it is desirable to understand the orientation of the imaging plane togather repeatable data longitudinally, but also to assess a specificsite from a variety of perspectives. Furthermore, it is rare that theuser will approach the site from the proper angle, so the device musttolerate and accommodate initial error. Thus, the user of the ultrasoundmust be able to detect the device from essentially all angles ofinsonation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 displays the cross section of a medical device with internalmicrocavities. The cavities resemble a spherical or semi-spherical shapeacross a range of sizes. The device contains an outer layer free ofmicrocavities.

FIGS. 2A and 2B respectively display the reflectance of the ultrasoundbeam for a medical device with and a medical device withoutmicrocavities. FIG. 2A, a medical device without microcavity, exhibits aspecular reflection of the ultrasound beam, which results in little tono signal returning to the probe. FIG. 2B displays the diffusereflection that is generated when the ultrasound beam contacts themicrocavities. Unlike in FIG. 2A, a significant portion of the signal isreflected back to the probe, irrespective of the originating angle ofthe emitted signal.

DETAILED DESCRIPTION

In one aspect, the invention provides an ultrasound-detectable medicaldevice comprising a polymer with microcavities dispersed in some or allof its body capable of providing improved visibility throughout some orall of its volume and under variable angles of insonation FIGS. 1 and2B. In some instances, the microcavities extend throughout the entirevolume of the medical device. In other instances, the microcavitiesoccupy a central region of the medical device. In additional instances,the space containing microcavities is surrounded by an outer layer ofmaterial without microcavities.

In another aspect, the invention provides an ultrasound-detectabledevice wherein the diameter (microcavity size) ranges between 0.1 to 950microns, and commonly between 50 to 350 microns. In some instances, themicrocavity diameter exceeds 1,000 microns. In other instances, themicrocavity diameter ranges from 10 to 500 microns. In additionalinstances, the microcavities exhibit diameters from 10 to 1,500 microns.

In a further aspect, the invention provides an ultrasound-detectabledevice wherein the ideal volume to volume ratio of cavity space topolymer structures should be less than 60%, and is commonly between 12%and 50%. In some instances, the microcavities comprise between 30 to 50%of the volume. In other instances, the volume ratio of microcavitiesexceeds 60%.

The ultrasound-detectable device contains microcavities. In one aspectof the device, the microcavities are composed of gas. In one aspect ofthe invention, the device is created via injection molding. In anotherembodiment, the device is manufactured by extrusion. In some aspects ofthe invention, microcavities are created by introducing gas into thepolymer material prior to manufacturing, commonly through injection. Inother aspects of the invention, microcavities are introduced during themanufacturing process, which can be performed by injecting gas into amold either before, while, or after the polymer enters the mold.

The microcavities may be composed of a variety of biocompatible gases.In some instances, super-critical CO2 is used, and in other instances,N2 is used.

In another embodiment, the microcavities are created via a chemicalreaction such that gas is released into the polymer. This may beaccomplished with a foaming agent or other chemical processes. The gasmay be activated by pressure or temperature changes in the manufacturingprocess.

For a variety of reasons, including mechanical, material degradation,visibility, and manufacturing considerations, it is desirable to havethe microcavities consume a region within the overall volume, ratherthan the entire device. In one embodiment, the region containing themicrocavities is central to the device. In this embodiment, the regioncontaining the microcavities is surrounded by a layer of polymeric ornon-polymeric material that does not contain microcavities. In otherembodiments of the device, this external layer, or “skin”, containsmicrocavities, though of a reduced density. In further embodiments, theregion containing the microcavities resides on the top surface of thedevice (superficial towards the position of the ultrasound probe), whilein other embodiments, the microcavity region resides on the bottomsurface of the device.

In one aspect of the invention, there is an outer layer of the devicewhich is meant to maintain the structural integrity of the innermicrocavity-containing region. This outer layer does not containmicrocavities and thus provides a barrier protecting the inner region,especially from fluid flow, which could accelerate degradation and alsonegatively impact the ultrasonic visibility. In another aspect of theinvention, the outer layer described has a smooth surface to minimizeirritation and other adverse events to surrounding tissue or vesselsonce the device is implanted.

Another aspect of the device relates to the visibility of the deviceunder ultrasonic imaging. In this aspect, the device is used as anechogenic marker for ultrasound location in the human body. Someanatomic structures that can be marked using this device include: veins,arteries, soft tissue, urinary tracts, nerves, and ducts. The deviceenables location of any of these structures after implantation. Inparticular, the device gives the clinician knowledge of the spatialrelationship between the ultrasound probe and anatomic structure,independent of the angle of insonation. The device enables locating theanatomic location repeatedly across many examinations after placement ofthe device. The size of the device ranges from 1 to 60 mm in length, 1to 60 mm in width, and 1 to 40 mm in height. Some embodiments of thedevice represent curved, cradle-like structures. Other embodiments ofthe device are spheres, rectangles, cubes, plates, pellets, and discs.Some instances of when this device could be used are for: microvascularanastomoses, solid organ transplants, vascular bypass, and vascularaccess.

In one embodiment of the device, it is comprised of one or moreresorbable polymers selected from the group of: poly(lactic-co-glycolicacid) (PLGA), polylactide (PLA), polyglycolide (PGA),polyhydroxyalkanoate (PHA), polycaprolactone (PCL), polyethylene glycol(PEG) and copolymers thereof.

In another embodiment of the device, it is comprised of one or morenon-resorbable polymers selected from the group of: polycarbonate,polyetheretherketone, polypropylene, silicone, polyethylene, polyester,polybutylene terephthalate (PBT), polyvinyl chloride, polyethylsulfone,polyacryclate, polyetheretherketone, poly-p-xylylene (parylene),polytetrafluoroethylene, cyclo olefin, acrylonitrile butadiene styrene,polyeurethane, acrylonitrile styrene acrylate, acetals, polyetherimide,ethylene, chlorotrifluoroethylene, ethylene tetrafluoroethylene,polyvinyl fluoride, polyvinylidene difluoride, and polyhydroxybutyrate.In a further embodiment, the device is comprised of both resorbable andnon-resorbable materials, which may be in the form of multiple sectionswith unique materials, a single blend of materials, or multiple sectionsof blended materials.

In one aspect of the invention, the device is manufactured via a foamingprocess. Microcavities are introduced into the polymer by introducing ablowing agent. The blowing agent created the cellular structure of themicrocavities. In one embodiment of the invention, the blowing agent isa physical blowing agent. In another embodiment, the blowing agent is achemical blowing agent. An alternative way of generating the foam isusing a solvent such as acetone. In addition to introducing the foamingagent, this invention describes injecting the polymer into a mold. Analternative way of producing the device is via extrusion.

This invention describes a method for using the device where the deviceis first inserted into a patient, it is then detected using B-modeultrasound during or after surgery, and the device is detected inmultiple frames, representing different angles of insonation. Theultrasound user can leave the patient and return to find the device at alater time point. This is important because it is often desired to trackanatomical or physiological features over a time horizon of multipledays or weeks, and sometimes months or years. This means that user needsto walk away from the patient, return to the patient, and easily locatethe device. Another critical feature of the invention is the ability todetect the device using ultrasound from any angle of insonation. This isimportant because a non-expert is able to locate the marked site and usethe visual information to achieve a desired angle or set of angles. Theinvention enables strong visibility in angles ranging from 25 degrees to155 degrees from the skin surface. The microcavity feature of theinvention provides the ability to visualize the device across such abroad range of insonation angles. Due to the geometry and microcavityfeature of the device, the user is able to understand the angle ofinsonation. Therefore, the user can repeatedly match the sameorientation upon each examination, generate the same image of thedevice, and thus compare anatomic or physiologic conditions reliablyover time. Alternatively, the user can approach the device from a neworientation in each additional examination, though will have thegeometric information from the device to make proper calculations toadjust for the new angle of insonation.

The device should not be compromised at 40 degrees Celsius when in adark and moist environment, such as human or animal tissue. Compromiseincludes but is not limited to geometric changes, mechanicaldeformation, degradation, or microcavity change. The device mustmaintain its original integrity for at least 72 hours in suchconditions. The device must yield contrast when visualized using B-modeultrasound between 1 cm and 5 cm deep from the surface of the skin.

Examples Example 1

An ultrasound-detectable medical device made by extrusion. Specifically,a Nano 16 mm extruder was used with a GFA3-10-30 screw element at 270mm. The extruder has four zones, each with individual temperaturecontrol, which ultimately lead to a die to achieve the desired geometryof the device. The zones were first preheated to 110, 140, 130 and 100°C. respectively. The pressure within the die ranged from 10-70 psi. Thefeeding rate of the polymer was 2.5 cc/min, and the screw speed fellbetween 75-100 rpm. The torque on the screw ranged from 1500-3000 Gm.The supercritical CO₂ was injected at 200 psi with a flow rate of 20cfh. When the extruded polymer left the die, it was cooled via an airjacket. In cases when it was desired to achieve variance along theextrusion axis, the device was laser cut once it cooled to roomtemperature using the air jacket.

Example 2

An ultrasound-detectable medical device made by injection molding. Thepolymer was introduced into the mold via injection through the port.While the material was being injected into the mold, CO₂ gas wassimultaneously injected to provide microbubbles. In another example, theCO₂ was introduced into the material prior to injection into the mold.Once the material filled the mold, the mold was released via its pins,the part was removed, and the process was repeated.

We claim:
 1. An ultrasound-detectable medical device comprising apolymer with microcavities dispersed in some or all of its body capableof providing improved visibility throughout some or all of its volumeand under variable angles of insonation.
 2. The ultrasound-detectabledevice of claim 1, wherein the diameter of the microcavities is about0.1 to about 950 microns.
 3. The ultrasound-detectable device of claim1, wherein the diameter of the microcavities is about 50 to about 350microns.
 4. The ultrasound-detectable device of claim 1, wherein thevolume to volume ratio of polymer structures to cavity space is than60%.
 5. The ultrasound-detectable device of claim 1, wherein the volumeto volume ratio of polymer structures to cavity space is about 12% toabout 50%.
 6. The ultrasound-detectable device of claim 1, wherein themicrocavities are formed by at least one gas.
 7. Theultrasound-detectable device of claim 6, wherein the at least one gas isselected from CO₂ or N₂.
 8. The ultrasound-detectable device of claim 1,wherein the microcavities are created via a chemical reaction within thematerial such that gas is released.
 9. The ultrasound-detectable deviceof claim 1, wherein the part of the device where improved echogenicityis desired contains a microcavity-containing polymer and the remainderis composed of a non-microcavity containing polymer or non-polymer. 10.The ultrasound-detectable device of claim 1, wherein the microcavitiesare encapsulated by an outer skin layer.
 11. The ultrasound-detectabledevice of claim 1, wherein the device is designed for use as anechogenic marker for ultrasound location in the human body.
 12. Theultrasound-detectable device of claim 1, wherein the material comprisesone or more resorbable polymers selected from the group comprisingpoly(lactic-co-glycolic acid) (PLGA), polylactide (PLA), polyglycolide(PGA), polyhydroxyalkanoate (PHA), polycaprolactone (PCL) and copolymersthereof.
 13. The ultrasound-detectable device of claim 1, wherein thematerial comprises one or more non-resorbable polymers selected from thegroup comprising polycarbonate, polyetheretherketone, polypropylene,silicone or polyethylene.
 14. A method for preparing theultrasound-detectable marker of claim 1 comprising the steps of: a.foaming the polymer by introducing a blowing agent; and b. injecting thefoamed polymer into a mold to form said marker.
 15. A method for using adevice of claim 1 comprising: a. inserting the device of claim 1 in apatient; b. detecting the device using B-mode ultrasound during or aftersurgery; and c. detecting the device in multiple frames, representingdifferent angles of insonation, during or after surgery.